Spatial and single-cell profiling identify NDRG1⁺ macrophages as key hallmark of angiogenic remodeling and platinum resistance in HGSOC.

High-grade serous ovarian cancer (HGSOC) exhibits profound immunologic and metabolic remodeling, yet the macrophage programs that drive disease progression and therapeutic resistance remain incompletely defined. Here, we integrate spatial transcriptomics, single-cell sequencing, bulk deconvolution, pseudotime reconstruction, and multiplex immunofluorescence to delineate a distinct tumor-promoting macrophage phenotype, termed Macro4, characterized by hypoxia adaptation, extracellular matrix remodeling, and pro-angiogenic signaling. Macro4 signature-based RSF model robustly predicted poor survival across multiple cohorts and remained an independent prognostic factor when combined with clinical variables. Mechanistically, Macro4 macrophages displayed strong VEGF- and SPP1-mediated communication with endothelial cells and occupied hypoxic, angiogenesis-enriched niches. Trajectory inference revealed that Macro4 arises from an inflammatory lineage that transitions toward glycolytic and matrix-remodeling terminal states under microenvironmental stress. Among Macro4-enriched genes, NDRG1 emerged as the dominant regulator, selectively expressed within Macro4, enriched across hypoxia-related pathways, associated with adverse overall survival in Cox analysis, and linked to chemoresistance and shorter progression-free survival. Spatial and protein-level validation confirmed that NDRG1⁺SPP1⁺ macrophages form discrete angiogenic niches and are preferentially localized to primary tumor sites. Together, our findings identify NDRG1+ Macro4 macrophages as a hypoxia-driven angiogenic niche associated with macrophage remodeling and platinum resistance in HGSOC, providing a framework for future macrophage-targeted therapeutic studies.